The incidence of serious infections caused by Group A streptococci (GAS) has increased. Such infections have occurred in diverse patient populations, including healthy young adults. These infections have caused marked tissue damage, bacteremia, and responded poorly to antimicrobial treatment. Infecting strains of GAS have predominantly belonged to either M Types 1 and 3 and were often mucoid. The regulation of mucoidy and those factors producing severe tissue damage are not known but may be coordinately regulated. Transposon insertion mutations were identified in an M Type 1 GAS that resulted in mucoidy, altered the expression of other exoproteins and reduced the expression of a previously unidentified putative regulatory gene. In a relevant murine model, the mucoid mutant was more virulent than the wild type. The goals of this research are to determine if the putative regulatory gene controls mucoidy and other factors which may cause severe tissue damage seen in GAS infections. In the long term, these factors will be precisely identified. The putative regulatory gene will be confirmed by the construction of in frame mutations in candidate open reading frames. To determine if there is an alteration in factors causing tissue damage, specific mutants will be constructed in which mucoidy is blocked and also in the putative regulatory gene. In addition, it will be determined if the product of the putative regulatory gene is a trans-acting polypeptide. Mutant strains will be compared in vitro for mucoidy, exoprotein profiles, and gene expression, and in vivo in a relevant animal model. The extent of tissue damage and bacteremia from a cutaneous site will be assessed for each mutant strain. Understanding the mechanism of severe streptococcal infections may lead to the identification of novel targets for specific therapy of a disease that causes severe morbidity and death, despite aggressive treatments.